Long lasting consequences of cannabis exposure in adolescence

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Abstract

Despite the increasing use of cannabis among adolescents, there are little and often contradictory studies on the long-term neurobiological consequences of cannabis consumption in juveniles. Adolescence is a critical phase for cerebral development, where the endocannabinoid system plays an important role influencing the release and action of different neurotransmitters. Therefore, a strong stimulation by the psychoactive component of marijuana, delta-9-tetrahydrocanabinol (THC), might lead to subtle but lasting neurobiological changes that can affect adult brain functions and behaviour.

The literature here summarized by use of experimental animal models, puts forward that heavy cannabis consumption in adolescence may induce subtle changes in the adult brain circuits ending in altered emotional and cognitive performance, enhanced vulnerability for the use of more harmful drugs of abuse in selected individuals, and may represent a risk factor for developing schizophrenia in adulthood.

Therefore, the potential problems arising in relation to marijuana consumption in adolescence suggest that this developmental phase is a vulnerable period for persistent adverse effects of cannabinoids.

Introduction

Cannabis is the most commonly used illicit substance among adolescents and young adults. In 2004, 46% of 12th graders in the USA reported having tried cannabis at some point in their lifetime, 34% reported having used within the past month, and 5.6% reported having smoked cannabis daily (Johnston et al., 2004). Initiation into cannabis use typically begins in adolescence, as youths aged 12–17 constitute about two thirds of the new cannabis users (SAMHSA, 2004). Approximately 14% of adolescent-onset cannabis users develops cannabis dependence, a rate roughly twice that reported for adult-onset users (Chen et al., 1997, Chen and Anthony, 2003). Cannabis dependence is defined in the Diagnostic and Statistical Manual of Mental Disorder (4th edition, text revision, DSM-IVTR) as having at least three out of seven symptoms within one year. Moreover, very recently, record numbers of teenagers were requiring drug treatment as a result of smoking skunk, the highly potent cannabis strain containing 25 times more delta-9-tetrahydrocannabinol (THC, the psychoactive ingredient) than the resin sold a decade ago.

Despite the constantly spreading use of cannabis among adolescents, there is little information about its neurobiological long-term consequences. The adolescent brain is particularly sensitive to internal and external variables such as drug exposure, environment and gonadal hormones, since in this period several active neural changes take place (Spear, 2000). In fact, adolescence is characterized by strong neuronal plasticity, with sprouting and pruning of synapses, myelinization of nerve fibers, changes in neurotransmitter concentrations and their receptor levels in brain areas essential for behavioural and cognitive functions (Rice and Barone, 2000). The receptor for cannabinoids (CB1) belongs to the Gi/Go-protein coupled receptor family, and, in mammalian brain, is densely diffused in regions involved in the processing of emotional inputs, rewarding stimuli, habit formation, and higher cognitive functions (Herkenham et al., 1990). Endogenous cannabinoids modulate neurotransmitter release in many brain regions via CB1 receptors (Morisset and Urban, 2001, Wilson and Nicoll, 2001, Wilson and Nicoll, 2002, Wilson et al., 2001). Accumulating evidence indicates that their peculiar mechanism of action as retrograde messengers is able to strongly influence both short-term and long-term forms of synaptic plasticity (Freund et al., 2003, Kreitzer and Regehr, 2002). Moreover, there is evidence for a role of the endocannabinoid system in neural development. Both cannabinoid receptors and endocannabinoid ligands can be detected in the brain during early developmental periods (Romero et al., 1997, Berrendero et al., 1999). The atypical distribution of cannabinoid CB1 receptors during the perinatal period seems to be related to a specific involvement of the endocannabinoid system in brain development. The system constituted by CB1 receptors and their putative endogenous ligands might influence the gene expression of several key genes for neural development as part of the specific function of the endocannabinoid system during this period (Fernandez-Ruiz et al., 2004). Moreover, in animal models, cannabinoid receptors have been shown to mature slowly, with maximal levels during adolescence which later drop to adult levels (Rodriguez de Fonseca et al., 1993, McLaughlin et al., 1994, Belue et al., 1995). Like dopamine receptors (Seeman, 1999), cannabinoid receptors may undergo postadolescent pruning. It is, therefore, conceivable that intake of exogenous cannabinoids, especially in vulnerable developmental periods, such as the adolescence, might induce residual effects.

This review aims to examine the existing literature on the long-term consequences of cannabinoid exposure during adolescence, considering its effect on the emotional behaviour, cognitive function, psychotic illness and the “drug gateway” hypothesis.

Section snippets

Adolescent cannabinoid exposure and adult emotional behaviour

There is an increasingly robust body of cross-sectional and prospective data supporting an association between adolescent use of cannabis and subsequent development of depressive and/or anxiety disorders (Fergusson et al., 2002, Patton et al., 2002, Rey et al., 2002, Hayatbakhsh et al., 2007) but also conflicting data suggesting no association between early cannabis use and later depression (Arseneault et al., 2002). Nevertheless, even in case of such an association it is not possible to

Adolescent cannabinoid exposure and adult cognitive function

Although few human studies have specifically addressed this issue, there is some evidence that exposure during adolescence may lead to lasting deficits in attention (Ehrenreich et al., 1999) and working memory (Schwartz et al., 1989).

Experimental data regarding long-term consequences of adolescent cannabinoid exposure on cognitive behaviour is scarce and not always in accordance, depending on the compound administered, the treatment paradigm used and the cognitive task performed (Table 1).

Adolescent cannabis exposure and psychosis

Worldwide evidence documents that cannabis use is a modest statistical risk factor for the emergence of psychosis, ranging from psychotic symptoms such as hallucinations and delusions to clinically significant disorders such as schizophrenia. Prospective studies estimate that cannabis use is associated with a two-fold increase in later schizophrenia outcomes, and early, adolescent-onset cannabis use is associated with a higher risk (Arseneault et al., 2004), possibly because individuals who

Adolescent cannabis exposure and the gateway hypothesis

Epidemiological studies showed that the adolescent stage is a developmental period with increased risk of drug abuse (Fried et al., 2001, Martin et al., 2002, Patton et al., 2004, Trad, 1994). Marijuana is widely consumed at this phase of life (Gruber and Pope, 2002) and there is evidence that using the drug at this stage could facilitate later drug abuse, a phenomenon that has been termed as “gateway hypothesis” (Kandel et al., 2006). Literature regarding the cannabis gateway hypothesis based

Conclusion

The intrinsic limitation of human epidemiological studies due to the great variability in the cultural, social, and economic background, as well as in the education level of the subjects, makes difficult to establish causal links between adolescent marijuana consumption and development of psychiatric illnesses, altered affective outcomes and drug dependence in adulthood. The strategy to evaluate directly the relationship between prior cannabis experience and adult altered responses independent

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